Darunavir brand name is PREZISTA, formerly known as TMC114, which is used to treat HIV infection. It is a protease inhibitor developed by pharmaceutical company Tibotec. Darunavir is a second-generation protease inhibitor (PIs), designed specifically to overcome problems with the older agents in this class, such as indinavir.
Darunavir Ethanolate, has the chemical name: [(1S,2R)-3-[[(4-aminophenyl) sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate and has the following structural formula:

Darunavir and its process are first disclosed in U.S. Pat. No. 6,248,775, wherein 2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S(phenylmethyl) propylamine (4) is reacted with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in anhydrous acetonitrile in the presence of N,N′-disuccinimidyl carbonate, anhydrous pyridine at ambient temperature followed by workup to get Darunavir (Scheme A).

US 20050250845 disclosed the various solvates of Darunavir including ethanolate and method for their preparation as well as their use as a medicament. The same application disclosed the amorphous Darunavir by Raman spectra without process details.
WO 2005063770 discloses process for the preparation of Darunavir ethanolate, wherein 2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl amine (4) is reacted with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in the presence of N,N′-disuccinimidyl carbonate, triethylamine, 41% methylamine in ethanol in a mixture of ethyl acetate and acetonitrile followed by workup and crystallization from ethanol to get Darunavir ethanolate (Scheme B).

In the prior art process, compound of formula 4 condensed with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in large excess of solvent or solvent mixture containing large excess of base or mixture of bases to get Darunavir. Further, the obtained products by the processes described in the prior art are not satisfactory, from purity point of view. We have repeated the Darunavir synthetic procedures as described in the prior art and found that relatively large amounts of impurities were obtained along with Darunavir (Table-1) which need repeated crystallizations in different solvents to get desired quality of the final product resulting in poor yields. Among other impurities, the carbonic acid [(1R,2S)-1-{((4-amino-benzenesulfonyl)-isobutyl-amino)-methyl}-2-((3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-3-phenyl-propylester (3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-yl ester (difuranyl impurity of formula 1) is identified.

However, a need still remains for an improved and commercially viable process for preparing pure crystalline or amorphous Darunavir that should solve the aforesaid problems associated with processes described in the prior art, which will be suitable for large-scale preparation, in terms of simplicity, yield and purity of the product. The inventors of the present invention also developed a novel process for amorphous Darunavir, which is feasible at large scale.